Stroke is the leading cause of adult disability. Recent pre-clinical studies have shown that stem/progenitor transplantation after stroke leads to improved recovery. These studies have not translated to clinical therapies for two main reasons. Experimental approaches target cell transplants to the normal brain adjacent to the stroke, which experiences damage in the transplantation and is the site of the most extensive natural recovery in humans;and most of the transplanted stem/progenitor cells die. The goal of this grant is to use stem/progenitor transplantation with a hydrogel/growth factor matrix directly into the stroke cavity itself to promote survival, differentiation and neural repair after stroke. The stroke cavity represents an ideal target for a neural repair therapy because it is a cavity and can accept stem/progenitor cell injections without damaging normal brain, and it lies directly next to the brain region that exhibits the most plasticity and functional reorganization after stroke, peri-infarct cortex. Stem/progenitor transplantation into the stroke cavity has not been successful in the past because of its harsh inflammatory and avascular environment. The proposed studies build on successful preliminary studies that have developed a hydrogel/growth factor matrix injected with stem/progenitor cells to create a vascularized, pro-growth environment in the stroke cavity - in a term creating a "stem cell niche" in the infarct core. This approach has translational utility as new neurosurgical operating rooms incorporate MRI-guided stereotaxic capabilities, which have been used to target stroke. The hypothesis is that stem/progenitor cells injected into the stroke cavity with either Leukemia Inhibitory Factor (LIF) or Brain Derived Neurotrophic Factor (BDNF) in a hyaluronan/heparin sulfate hydrogel will support survival (LIF) and differentiation (BDNF) and enhance endogenous neural repair in peri-infarct tissue. Specific Aim #1 will determine the effect of growth factor/hydrogel transplantation into the infarct cavity on normal processes of neural repair and recovery in stroke. These studies will first identify the effects of the hydrogel LIF or BDNF on axonal sprouting, neurogenesis and angiogenesis in peri-infarct cortex. Specific Aim #2 will determine the effect of growth factor/hydrogel transplantation into the infarct cavity with embryonic stem cell- derived neural precursor cells. These studies will determine the survival, differentiation and engraftment that occur with hydrogel LIF or BDNF, and the effects on axonal sprouting, neurogenesis and angiogenesis. These studies develop a multidisciplinary approach that combines bioengineering, stem cell biology and neural repair studies in stroke to identify a novel approach that may promote recovery in this disease. PUBLIC HEALTH RELEVANCE: This grant develops a novel approach to tissue repair after stroke by creating a bioengineered system to promote the survival and integration of transplanted neural stem cells in the infarct cavity. These studies will identify the mechanisms of brain repair after stroke using this stem cell therapy, and set the direction for more applied studies that might develop this approach into a repair therapy for stroke.